NCT04006262

Description:

This is a non-randomized study, open label phase II study. The purpose of this study is to
evaluate the complete pathologic response rate (cPRR) with neoadjuvant nivolumab and
ipilimumab combination in patients with MSI and/or dMMR localized oeso-gastric cancer.

Clinical Trial IDs

Conditions

Localized Oesogastric Adenocarcimona

MSI and or dMMR

Interventions

Drug

Synonyms

Arms

Nivolumab 10 MG/ML

Experimental arm

Ipilimumab 200 MG in 40 ML Injection

Experimental arm

Purpose

This is a non-randomized study, open label phase II study. The purpose of this study is to
evaluate the complete pathologic response rate (cPRR) with neoadjuvant nivolumab and
ipilimumab combination in patients with MSI and/or dMMR localized oeso-gastric cancer.

Detailed Description

In patients with resectable oeso-gastric adenocarcinoma, radical surgery is the only curative
option. Despite the evolution in treatment with multimodality treatment strategies,
oeso-gastric cancer remains one of the most lethal malignancies with 5-year survival rates
reaching only 22%. When the disease is localized, perioperative chemotherapy with cytotoxic
agents is the preferred strategy since it increases the overall survival (OS) rate. However,
in oeso-gastric cancers with microsatellite instability (MSI), is a favorable prognostic
factor, the recommended cytotoxic chemotherapy combination seems inefficient and even
deleterious.
It is now well established that dMMR and or the MSI phenotype are the surrogate markers of
response to immunotherapy.
The combination of nivolumab and ipilimumab had shown promising efficacy in multiple tumor
types (dMMR/MSI).
Based on the data above, we have designed this phase II study to evaluate the complete
pathological response rate (cPRR) in patients with non-metastatic MSI/dMMR oeso-gastric
adenocarcinoma treated with neoadjuvant nivolumab and ipilimumab treatment.

Eligibility Criteria

Inclusion Criteria:
1. Signed and dated informed consent,
2. Age ≥18 years,
3. Histologically proven non-metastatic gastric adenocarcinoma or of the oeso-gastric
junction T2 to T4, Nx, M0 after thoraco-abdomino-pelvic computed tomography (CT) and
echo-endoscopy
4. Subjects must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests, tumor biopsies, and other requirements of the study,
5. dMMR DNA (protein expression by immunohistochemistry [ICH] and/or MSI by polymerase
chain reaction [PCR]), MMR and/or MSI tumors should be assessed per local guidelines:
ICH with two (anti-MLH1 and anti-MSH2 or anti-MSH6, and anti-PMS2) or four antibodies
(anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2) and/or PCR (with PROMEGA: BAT-25,
BAT-26, NR-21, NR-24, and NR-27) by the investigators prior to screening, Extinct MLH1
(+/- PMS2), MSH2 (+/- MSH6), MSH6, or PMS2 alone protein expression by IHC (dMMR),
and/or tumor with ≥ 2 instable MSI-H markers on PCR: BAT25, BAT26, NR21, NR24, and
NR27 (pentaplex panel is recommended), Agreement of the SPONSOR (GERCOR) is mandatory
to include the patient (the patient's file will be verified to confirm a dMMR/MSI-H
status before inclusion [an anonymized fax] and confirmation of a patient's inclusion
will be sent by mail to the Investigator within 24h),
6. The Eastern Cooperative Oncology Group Performance status (ECOG PS) 0-1,
7. Hematological status: absolute neutrophil count (ANC) ≥1.5 x 109/L; platelets ≥100 x
109/L; hemoglobin ≥9 g/dL,
8. Adequate renal function: serum creatinine level <120 μM, clearance > 50ml/min
(Modification of the Diet in Renal Disease [MDRD] or Cockcroft and Gault),
9. Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline
phosphatase <5 x ULN, alanine aminotransferase (ALT), and aspartate aminotransferase
(AST) ≤3.0 x ULN,
10. No prior therapy for localized oeso-gastric cancer,
11. Radiological tumor assessment within 21 days before the start of treatment according
to RECIST version 1.1 by Chest Abdomen and Pelvis CT,
12. For female patients of childbearing potential, negative pregnancy test within 7 days
before starting the study drug,
13. Men and women are required to use adequate birth control during the study (when
applicable), Female participants of childbearing potential and male participants with
partners of childbearing potential must agree to use a highly effective method of
birth control (i.e., pregnancy rate of less than 1% per year) during the period of
treatment and during 5 and 7 months, woman and men, respectively, from the last
treatment administration. Men must refrain from donating sperm during this same
period, Contraceptive methods that result in a low failure rate when used consistently
and correctly include methods such as combined hormonal contraception associated with
inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal
contraception associated with inhibition of ovulation (oral, injectable, implantable),
some intrauterine devices, intrauterine hormone-releasing stem, true sexual abstinence
(when this is in line with the preferred and usual lifestyle of the participant),
bilateral tubal occlusion, or a female partner who is not of childbearing potential or
a male partner who has had a vasectomy. Women and female partners using hormonal
contraceptive must also use a barrier method i.e. condom or occlusive cap (diaphragm
or cervical/vault caps), A woman is considered to be of childbearing potential if she
is postmenarcheal, has not reached a postmenopausal state (>12 continuous months of
amenorrhea with no identified cause other than menopause), and has not undergone
surgical sterilization (removal of ovaries and/or uterus),
14. Subject willing to comply to provide primary tumor tissue (archival or fresh biopsy
specimen), including possible pre-treatment biopsy for PD-L1 expression analysis and
other biomarker correlative studies
15. Registration in a National Health Care System (PUMa - Protection Universelle Maladie
included),
Exclusion Criteria:
- Non-eligible to clinical trial if one of following parameter is reported:
1. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted
therapy, immunotherapy),
2. Treatment with any investigational medicinal product within 28 days prior to study
entry,
3. Major surgical procedure within 4 weeks prior to initiation of study treatment,
4. Other serious and uncontrolled non-malignant disease (including active infection),
5. Other concomitant or previous malignancy, except: i/ adequately treated in-situ
carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin,
iii/ cancer in complete remission for >5 years,
6. Metastases (M stage disease) whatever the location,
7. Pregnant or breastfeeding women,
8. Human immunodeficiency virus (HIV),
9. Active hepatitis B virus (HBV, defined as having a positive hepatitis B surface
antigen [HBsAg] test prior to inclusion) or hepatitis C virus (HCV).
Note: Patients with past HBV infection or resolved HBV infection (defined as having a
negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test)
are eligible.
Note: Patients positive for HCV antibody are eligible only if PCR testing is negative
for HCV RNA.
- Non-eligible to immunotherapy:
10. History of autoimmune disease including, but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis, Note: History of
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may
be eligible.
Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
11. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
organizing pneumonia), or evidence of active pneumonitis on screening chest imaging,
12. Administration of a live, attenuated vaccine within 4 weeks prior to start of
treatment or anticipation that such a live attenuated vaccine will be required during
the remainder of the study,
13. Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic
antibody or pathway-targeting agents,
14. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,
15. Treatment with systemic corticosteroids or other systemic immunosuppressive
medications (including, but not limited to prednisone, dexamethasone,
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis
factor agents) within 2 weeks prior to start of adjuvant treatment, or requirement for
systemic immunosuppressive medications during the remainder of the study. Inhaled or
topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are
permitted in the absence of active autoimmune disease.
Note: Patients who have received acute, low-dose, systemic immunosuppressant medications
(e.g., a one-time dose of dexamethasone for nausea) may be enrolled into the study after
approval of the Medical Contact. Subjects are permitted the use of topical, ocular,
intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic
absorption). Adrenal replacement steroid doses including doses >10 mg daily prednisone is
permitted. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g.
contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-type
hypersensitivity reaction caused by a contact allergen) is permitted.

Maximum Eligible Age:

N/A

Minimum Eligible Age:

18 Years

Eligible Gender:

All

Healthy Volunteers:

No

Primary Outcome Measures

Measure:

Complete pathological response (cPRR) rate

Time Frame:

time point when the tumor is examined after the surgery (up to 30 months)

Safety Issue:

Description:

Each center will assess the pathologic response with a centralized center review in case of cPRR and the analysis will be in intention-to-treat (ITT). cPRR will be defined as complete tumor disappearance of tumor in the low esophagus or the stomach (from 1/3 inferior of the esophagus to pylorus) after surgery anatomopathologic examination according to mandard scale.
Surgery was performed within 5 weeks after Cycle 6 (neoadjuvant therapy)

Secondary Outcome Measures

Measure:

Disease-free survival (DFS)

Time Frame:

Up to 36 months

Safety Issue:

Description:

DFS is defined as the time from the date of starting treatment to local recurrence and/or metastases or death irrespective of cause and censored at the date of last contact.

Measure:

Overall Survival (OS)

Time Frame:

Up to 36 months

Safety Issue:

Description:

OS is defined as the time between the date of the first dose of study treatment and the death date. Patients alive at last report will be considered censored at the endpoint. Alive patients will be censored at the last date known to be alive, either during study treatment period or during follow-up period.

Measure:

Number of participants with treatment-related adverse events as assessed by National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] v5.0

Time Frame:

Patients will be assessed for AEs throughout the study at every visit during treatment and at 3-month follow-up visit (3 months after treatment ends). Investigators using the NCI-CTCAE version 5.0 will grade the severity of AEs.

Safety Issue:

Description:

Measure:

Analyze MSI status

Time Frame:

up to 36 months

Safety Issue:

Description:

Confirmation of MSI and/or dMMR had to be confirmed retrospectively on archival or fresh tumor FFPET block from the primary tumor obtained at the time of the initial diagnosis

Blood samples at baseline, C3D1 and C6D1 of neoadjuvant therapy - cycle every 2 weeks, after surgery at C1 D1(first cycle of adjuvant treatment) and at the end of treatment visit (28 days after the last dose of treatment (up to 36 months)

Safety Issue:

Description:

Measure:

Number of Species of bacteria and yeast composition

Time Frame:

Baseline and at week 12

Safety Issue:

Description:

To investigate the microbiota composition changes during neoadjuvant therapy with nivolumab and ipilimumab and its relation to response and/or chemotoxicity.
Number of Species of bacteria and yeast will be quantitfy and identify. Number of Change of composition will be investigate based on baseline samples compared to 12 weeks sample.
DNA will be extracted from fecal samples taken prior to therapy and on-treatment (week 12). A gene sequencing approach will be utilized to survey microbial species in the gut in order to define microbiota as a function of the efficacy and safety.